Anti-spasmodic agents having a heterocyclic ring

ABSTRACT

A new method of treating a patient suffering from smooth muscle spasms involves treatment with a class of anti-spasmodic thioester compounds having a heterocyclic ring containing the nitrogen atom of a secondary or tertiary amine or a bicycloheterocyclic ring system containing the nitrogen atom of a secondary or tertiary amine. These compounds have the general formula I ##STR1## wherein: n is an integer from 0 to 2; 
     R 1  is aryl or cycloalkyl; 
     R 2  is hydrogen or hydroxyl; and 
     R 3  is selected from the group consisting of heterocyclic containing the nitrogen atom of a secondary or tertiary amine to which an alkyl group having from 0 to 3 carbon atoms is bonded and no other hetero atoms are present in the ring structure; heterocyclic containing the nitrogen atom of a secondary or tertiary amine to which an alkyl group having from 0 to 3 carbon atoms is bonded and one or more hetero atoms selected from the group consisting of N, O and S are present in the ring structure; bicycloheterocyclic ring system containing the nitrogen atom of a secondary or tertiary amine to which an alkyl group having from 0 to 3 carbon atoms is bonded and no other hetero atoms are present in the ring system; and bicycloheterocyclic ring system containing the nitrogen atom of a secondary or tertiary amine to which an alkyl group having from 0 to 3 carbon atoms is bonded and one or more hetero atoms selected from the group consisting of N, O and S are present in the ring system.

This is a division of application Ser. No. 817,443, filed Jan. 9, 1986,now U.S. Pat. No. 4,721,783.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to a method of treating patients forsmooth muscle spasm with the use of new pharmaceutical compounds havinguseful anti-spasmodic properties.

2. Description of the Prior Art

The purpose of an anti-spasmodic drug is to relieve spasms of the smoothmuscles. Smooth muscles line most of the visceral organs. Theperistalsis and muscular activity of the stomach, intestines, gallbladder, urinary bladder, lung, the uterus, and to a degree the heartare all largely controlled by smooth muscles. Smooth muscles areinnervated by the autonomic nervous system. The autonomic nervous systemconsists of two antagonistic branches--the sympathetic branch and theparasympathetic branch. On all visceral organs except the heart theparasympathetic nerve impulses increase the irritability and tension ofthe smooth muscles; contrariwise, the sympathetic nerve impulsesincrease the tension and irritability of the muscles of the heart muscleand relax the smooth muscles of the other visceral organs.

A spasm in a smooth muscle may be due to one of two causes. Either thesmooth muscle may be receiving exaggerated impulses from the autonomicnervous system which create violent contractions in the muscle, or themuscle may be intrinsically stimulated into a spasm (most likely fromchemical changes in the surrounding tissue). A spasm due to exaggeratedimpulses from the parasympathetic branch of the autonomic nervous systemmay often be corrected by administering atropine (an active alkaloid ofbelladonna, which serves to break a connection between theparasympathetic nerve and the smooth muscle. This ability and effect ofatropine is called a "neurotropic effect". A spasm intrinsic in thesmooth muscle itself may often be corrected by papaverine (a derivativeof opium which is classed as a narcotic). Papaverine has an ability todecrease intrinsically the contractility of smooth muscle; it has theability to relax smooth muscles directly. This ability and effect ofpapaverine is called a "musculotropic effect."

In relieving spasms of smooth muscles generally, a musculotropic effectis acknowledged to be superior to a neurotropic effect. A neurotropiceffect cannot relieve spasms intrinsic in the smooth muscle itself,while a musculotropic effect, by relaxing and decreasing theirritability and responsiveness of smooth muscle to stimulation from theautonomic nervous system, can help to relieve a smooth muscle spasm evenwhen it is due to exaggerated impulses from the autonomic nervoussystem.

Atropine produces undesirable side-reactions which presents a clinicaldifficulty. Atropine when given in effective doses, serves to break orpartly break all the parasympathetic nerve-smooth muscle connectionsthroughout the body. Thus when atropine is given in sufficient dosage torelieve a spasm in a specific visceral organ, such as a gastric orintestinal spasm (the spasm caused by exaggerated nerve impulses fromthe parasympathetic nervous system) undesirable side-actions due to thebreaking of the parasympathetic nerve-muscle connections elsewhere inthe body may occur. The most easily recognized of these undesirable sidereactions are dilation of the pupil and dryness of the mouth, caused bythe breaking of the parasympathetic connections to the iris and thesaliva producing mechanism respectively.

Atropine is acknowledged to have also a musculotropic effect, but itsneurotropic effect is so strong that atropine must be given in minutedoses not exceeding (1/60 to 1/40 grain). A dosage of 1/6 to 1/40 ofgrain is too small to permit a significant musculotropic effect and whenlarger doses are administered undesirable side reactions areencountered.

U.S. Pat. No. 2,390,555 discloses a class of compounds comprisingdi-N-substituted aminoethyl esters of diphenylthioacetic acid of thegeneral formula (C₆ H₅)₂ --CH--COS--CH₂ CH₂ --R in which R represents adisubstituted amino radical of either the diethylamino group, themorpholino group or the piperidino group with Nas the point ofattachment. This patent discloses that the thio analogs of certaindisubstituted acetic acid esters of aminoalcohols have desirableanti-spasmodic properties. These compounds have proven to be veryeffective and are widely used as anti-spasmodics without encounteringthe undesirable side reactions due to excessive neurotropic effect.

U.S. Pat. No. 4,432,977 discloses new uses, especially for the dilationof the smooth muscles of the upper urinary tract, of the compoundsdisclosed in U.S. Pat. No. 2,390,555.

In Compte Rendu de la Societe de Biologie, 140, pp 477-9, (1946) Dupre,Levy and Tchoubar disclose a series of compounds having the formula C₆H₅ (R)CH--C(O)--S--CH₂ CH₂ N(CH₂ CH₃)₂ where R is either a phenyl group,a propyl group, an isopropyl group, a butyl group or an isoamyl group.These compounds are all disclosed as being spasmolytic agents.

Compounds of the same general formula given above are disclosed byTchoubar and Letellier-Dupre in Bulletin de la Societe Chimique, pp792-4 (1947) wherein R was a phenyl group, an ethyl group, a propylgroup, an isopropyl group, a butyl group, an isoamyl group or hydrogen.

In Farmakol. i. Toksikol., pp 10-17 (1956), Liberman discloses a classof compounds having the general formula (C₆ H₅)₂ CHCOSCH₂ CH₂ N--R₂,wherein both R's are the same and are selected from methyl, ethyl,propyl and butyl groups; and a class of compounds having the generalformula (C₆ H₅)--CH(C₆ H₁₁)COSCH₂ CH₂ N--R₂, wherein both R's are thesame and are selected from methyl, ethyl, propyl and butyl groups.

C. A. Buehler et al. in the Journal of Medicinal Chemistry, 6, pp 230-3(1963) disclose physiologically active compounds of the general formulaRR'C(OH)COS(CH₂)_(x) NR₂ "·HCl wherein R and R' are aryl groups, x is 2or 3, and R₂ " is a methyl or ethyl group.

R. O. Clinton et al. in the Journal of the American Chemical Society,68, pp 2076-7 (1946) disclose synthesis of a number of dialkylaminoalkyl diarylthiolacetates including fluorene-9-carbothioic acid,S-[2-diethylaminoethyl]ester.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

Patients suffering smooth muscle spasms are treated by administeringeffective amounts of a new class of anti-spasmodic compounds having thegeneral formula I ##STR2## wherein: n is an integer from 0 to 2;

R₁ is aryl or cycloalkyl;

R₂ is hydrogen or hydroxyl; and

R₃ is selected from the group consisting of heterocyclic containing thenitrogen atom of a secondary or tertiary amine to which an alkyl grouphaving from 1 to 3 carbon atoms is bonded and no other hetero atoms arepresent in the ring structure; heterocyclic containing the nitrogen atomof a secondary or tertiary amine to which an alkyl group having from 0to 3 carbon atoms is bonded and one or more hetero atoms selected fromthe group consisting of N, O and S are present in the ring structure;bicycloheterocyclic ring system containing the nitrogen atom of asecondary or tertiary amine to which an alkyl group having from 1 to 3carbon atoms is bonded and no other hetero atoms are present in the ringsystem; and bicycloheterocyclic ring system containing the nitrogen atomof a secondary or tertiary amine to which an alkyl group having from 1to 3 carbon atoms is bonded and one or more hetero atoms selected fromthe group consisting of N, O and S are present in the ring system.

The present invention also comprises methods of administering theabove-described compounds for, but not limited to, the treatment ofpatients suffering from spasms in the upper and lower gastrointestinaltract, spasm associated with the gall bladder and common bile duct, aswell as diarrhea, the irritable bowel syndrome, ureterospasm, bladderirritation, asthma, emphysema, and ophthalmologic injuries.

Representative heterocyclic rings include, but are not limited to, thefollowing: 1-methyl-imidazolinyl, 1-ethyl-imidazolinyl,1-n-propylimidazolinyl, 1-iso-propyl-imidazolinyl, 1-methyl-imidazolyl,1-ethyl-imidazolyl, 1-n-propyl-imidazolyl, 1-iso-propylimidazolyl,1-methyl-morpholinyl, 1-ethyl-morpholinyl, 1-n-propyl-morpholinyl,1-iso-propyl-morpholinyl, 1-ethyl-piperazinyl, 1-n-propyl-piperazinyl,1-iso-propyl-piperazinyl, 1-ethylpiperidinyl, 1-n-propyl-piperidinyl,1-iso-propyl-piperidinyl, 1-methyl-pyrazolyl, 1-ethyl-pyrazolyl,1-n-propyl-pyrazolyl, 1-iso-propyl-pyrazolyl, 1-n-propyl-pyrrolidinyl,1-iso-propyl-pyrrolidinyl, 1-methyl-3-pyrrolinyl, 1-ethyl-3-pyrrolinyl,1-n-propyl-3-pyrrolinyl, 1-iso-propyl-3-pyrrolinyl,1-methyl-thiomorpholinyl, 1-ethyl-thiomorpholinyl,1-n-propyl-thiomorpholinyl, 1-iso-propyl-thiomorpholinyl,4-methyl-1,2,4-triazolyl, 4-ethyl-1,2,4-triazolyl,4-n-propyl-1,2,4-triazolyl, 4-iso-propyl-1,2,4-triazolyl.

Representative compounds according to the method of this invention whichcontain bicycloheterocyclic ring systems include, but are not limitedto, the following: ##STR3## Cyclopentaneacetic acid, alpha-phenylthio,S-(3-alpha-tropanyl)ester ##STR4## Benzilic acid, thio,S-(3-quinuclidinyl)ester

The general reaction in the synthesis of the anti-spasmodic compoundsdescribed in the following examples of the present invention involvesthe nucleophilic substitution of, for instance, diphenylacetyl chloridewith certain heterocyclic thiol compounds. This reaction may beillustrated in the following scheme: ##STR5## (diphenylacetyl chloride)(1-ethyl-3-mercapto-piperidine hydrochloride) ##STR6##(3-diphenylthioacetyl-1-ethyl-piperidine hydrochloride)

The thiol containing a heterocyclic ring may be reacted withdiphenylacetyl chloride in dichloromethane by combining the reactants ina 1:1 molar ratio and gently heating under reflux condensation forapproximately 1-2 hours.

The desired acyl chlorides may be prepared from the carboxylic acidanalogous by reaction with oxalyl chloride as follows: ##STR7##

The reaction may be performed under reflux condensation. Following thereaction, which may be complete within a few hours, the acid chloridesmay be vacuum-distilled and reacted with a thiol compound as describedabove.

The anti-spasmodic compounds used in the method of the present inventionmay be effective in a dosage range of from about 1 to about 15mg/kilogram of body weight per day. A preferred dosage is in the rangeof from about 1.5 to about 11.5 mg/kilogram of body weight per day. Astill more preferred dosage range is from about 3 to about 6 mg/kilogramof body weight per day.

The anti-spasmodic compounds used in the method of the present inventionmay be combined with a pharmaceutically acceptable carrier and may beadministered orally, typically in tablets of 400 mg active ingredient,total 1155 mg, or by intravenous injection, or by topical application.

Because the anti-spasmodic compounds used in the method of the presentinvention may hydrolyze slowly in water, they are preferably not used asa solution or aqueous suspension unless freshly prepared compounds. Itmay be possible, however, to suspend the microspheres of these compoundsin non-aqueous liquids for administration to patients.

As examples which are illustrative of, but are not limited to, thecompounds used in the method of the present invention, there may bementioned the following compounds designated as 1(a-x) through 10(a-x).R₁, R₂ and n for these compounds are located in Table I: ##STR8##

                  TABLE I                                                         ______________________________________                                                   n   R.sub.1      R.sub.2                                           ______________________________________                                        1a-10a:      0     H            methyl                                        1b-10b:      0     H            ethyl                                         1c-10c:      0     H            n-propyl                                      1d-10d:      0     H            iso-propyl                                    1e-10e:      1     H            methyl                                        1f-10f:      1     H            ethyl                                         1g-10g:      1     H            n-propyl                                      1h-10h       1     H            iso-propyl                                    1i-10i:      2     H            methyl                                        1j-10j:      2     H            ethyl                                         1k-10k:      2     H            n-propyl                                      1l-10l:      2     H            iso-propyl                                    1m-10m:      0     OH           methyl                                        1n-10n:      0     OH           ethyl                                         1o-10o:      0     OH           n-propyl                                      1p-10p:      0     OH           iso-propyl                                    1q-10q:      1     OH           methyl                                        1r-10r:      1     OH           ethyl                                         1s-10s:      1     OH           n-propyl                                      1t-10t:      1     OH           iso-propyl                                    1u-10u:      2     OH           methyl                                        1v-10v:      2     OH           ethyl                                         1w-10w:      2     OH           n-propyl                                      1x-10x:      2     OH           iso-propyl                                    ______________________________________                                    

The compounds used in the method of this invention are anti-muscarinicagents (cholinergic-muscarinic receptor antagonists) which inhibit theactions of acetylcholine on autonomic effectors innervated bypostganglionic cholinergic nerves as well as on smooth muscle that lackscholinergic innervation. Since a major component of parasympatheticcontrol of smooth muscle occurs via muscarinic receptors, thesecompounds may be effective as modifiers of smooth muscle activity.

Thiphenamil hydrochloride has been shown to decrease spasms of thegastrointestinal tract, biliary tract, ureter and uterus withoutproducing characteristic atropinic side effects on salivary and sweatglands, GI glands, or the cardiovascular system. This invention resultsin the use of compounds which may be as efficacious as thiphenamilhydrochloride, or more so, in relaxing various smooth muscle systemswhile at the same time demonstrating thiphenamil hydrochloride's lack ofassociated side-effects.

I claim:
 1. A method of treating a patient suffering smooth muscle spasmcomprising administering to the patient an effective amount of ananti-spasmodic agent comprising a compound of formula I ##STR9##wherein: n is an integer from 0 to 2;R₁ is aryl or cycloalkyl; R₂ ishydrogen or hydroxyl; and R₃ is a heterocyclic or bicycloheterocyclicnitrogen ring connected to the main chain and is selected from the groupconsisting of heterocyclic containing the nitrogen atom of a secondaryor tertiary amine to which an alkyl group having 1 to 3 carbon atoms isbonded and no other hetero atoms are present in the ring structure;heterocyclic containing the nitrogen atom of a secondary or tertiaryamine to which an alkyl group having from 1 to 3 carbon atoms is bondedand one or more hetero atoms selected from the group consisting of N, Oand S are present in the ring structure; bicycloheterocyclic ring systemcontaining the nitrogen atom of a secondary or tertiary amine to whichan alkyl group having 1 to 3 carbon atoms is bonded and no other heteroatoms are present in the ring system; and bicycloheterocyclic ringsystem containing the nitrogen atom of a secondary or tertiary amine towhich an alkyl group having from 1 to 3 carbon atoms is bonded and oneor more hetero atoms selected from the group consisting of N, O and Sare present in the ring system.
 2. The method as defined in claim 1,wherein the compound is administered in a dosage of from about 1 toabout 15 mg/kg of body weight per day.
 3. The method as defined in claim1, wherein the compound is administered in a preferred dosage from about1.5 to about 11.5 mg/kg of body weight per day.
 4. The method as definedin claim 1, wherein the compound is administered in a more preferreddosage of from about 3 to about 6 mg/kg of body weight per day.
 5. Themethod as defined in claim 1, wherein the compound is combined with apharmaceutically acceptable carrier.
 6. A method of treating a patientsuffering from smooth muscle spasm comprising the step of administeringan effective amount of an antispasmodic agent having the formula##STR10## wherein: n is an integer from 0 to 2;R₁ is aryl or cycloalkyl;R₂ is hydrogen or hydroxyl; and R₃ is a heterocyclic nitrogen ringconnected to the main chain and is selected from the group consisting of1-methylimidazolinyl, 1-ethyl-imidazolinyl, 1-n-propyl-imidazolinyl,1-iso-propyl-imidazolinyl, 1-methyl-imidazolyl, 1-ethyl-imidazolyl,1-n-propyl-imidazolyl, 1-iso-propyl-imidazolyl, 1-methylmorpholinyl,1-ethyl-morpholinyl, 1-n-propyl-morpholinyl, 1-iso-propyl-morpholinyl,1-ethyl-piperazinyl, 1-n-propyl-piperazinyl, 1-iso-propyl-piperazinyl,1-n-propyl-piperidinyl, 1-iso-propyl-piperidinyl, 1-methyl-pyrazolyl,1-ethyl-pyrazolyl, 1-n-propylpyrazolyl, 1-iso-propyl-pyrazolyl,1-n-propyl-pyrrolidinyl, 1-iso-propyl-pyrrolidinyl,1-methyl-3-pyrrolinyl, 1-ethyl-3-pyrrolidinyl,1-n-propyl-3-pyrrolidinyl, 1-iso-propyl-3-pyrrolinyl,1-methyl-thiomorpholinyl, 1-ethyl-thiomorpholinyl,1-n-propyl-thiomorpholinyl, 1-iso-propyl-thiomorpholinyl, 4-methyl,1,2,4-triazolyl, 4-ethyl-1,2,4-triazolyl, 4-n-propyl-1,2,4-triazolyl,4-iso-propyl-1,2,4-triazolyl.
 7. A method of treating a patientsuffering smooth muscle spasm comprising administering to the patient aneffective amount of an anti-spasmodic agent comprising a compound havinga formula selected from the group consisting of ##STR11## where n is aninteger from 0 to 2, R₁ is H or OH and R₂ is selected from the groupconsisting of methyl, ethyl, n-propyl and isopropyl, and where (a)through (x) are combinations of n, R₁ and R₂ as defined in Table
 1. 8. Amethod of treating a patient suffering smooth muscle spasm comprisingadministering to the patient an effective amount of an anti-spasmodicagent comprising a compound having a formula selected from the groupconsisting of ##STR12## where n is an integer from 0 to 2 and R₂ isselected from the group consisting of methyl, ethyl, n-propyl andisopropyl, and wherein (a) through (x) are combinations of n and R₂ asdefined in Table
 1. 9. A method of treating a patient suffering fromsmooth muscle spasm comprising the step of administering an effectiveamount of an anti-spasmodic agent having the formula ##STR13## where R₃is 1-ethyl-piperidinyl.